The candidate is a pediatric hematologist and geneticist, with basic science training in biochemistry and molecular biology; and a clinical research background in pediatric blood, lipid, and vascular disorders. The primary short term goal for this award is to provide protected time for two ongoing genetic studies related to blood and vascular disease in pediatric populations. The major long-term goal is to establish the PI as a mentor for fellows interested in patient-related translational research in pediatric hematology, genetics, cardiology or nutrition. The study environment is the Hematology Division and the lipid clinic at Children's Hospital, Boston, a major center for training young investigators in pediatrics. The first project aims to elucidate genetic basis of the syndrome, Thiamine Responsive Megaloblastic Anemia (TRMA). By homozygosity mapping, the PI has mapped this recessive disorder to chromosome 1 (1q23.2-23.3). Fibroblasts from patients, but not controls, demonstrate cell death in thiamine deficient medium, due to defective high-affinity thiamine uptake. The working hypothesis for this study is that the TRMA gene encodes a mammalian thiamine transporter. Using a combination of positional and complementation cloning techniques, the gene for TRMA will be identified, and mutations sought in the DNA from patients. The function of the normal TRMA gene will be examined, and somatic defects in this gene will be sought among patients with related disorders, including marrow myelodysplasia. The second project is aimed at identifying gene(s) responsible for low levels of high-density lipoprotein (HDL) cholesterol by linkage analysis. Familial low HDL-C is a major contributor to early atherosclerosis. Patients with low HDL-C and a family history of premature heart disease have been ascertained in the setting of a pediatric lipid clinic. To date, 38 kindreds, including more than 600 individuals, have been enrolled, and a multicenter effort is underway to enroll 100 kindreds. Linkage will be sought to candidate genes related to HDL metabolism, and in genome-wide screens. Polymorphic markers for known or novel candidate genes identified in these studies will then be evaluated in broader populations. Both projects provide training opportunities for fellows in aspects of patient-focused science, ranging from cellular biochemistry approaches to metabolic disorders, to linkage analysis, to population studies of genetic polymorphisms.